Effect of the Time of Administration of Calcium Acetate on Phosphorus Binding

Phosphorus binders are given to patients with renal failure to increase gastrointestinal excretion of phosphorus. To determine the relative importance of the binding of dietary as compared with endogenous phosphorus and to determine the optimal dose schedule, we gave either 4.4 g of calcium acetate...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:The New England journal of medicine 1989-04, Vol.320 (17), p.1110-1113
Hauptverfasser: Schiller, Lawrence R, Ana, Carol A. Santa, Sheikh, Mudassir S, Emmett, Michael, Fordtran, John S
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 1113
container_issue 17
container_start_page 1110
container_title The New England journal of medicine
container_volume 320
creator Schiller, Lawrence R
Ana, Carol A. Santa
Sheikh, Mudassir S
Emmett, Michael
Fordtran, John S
description Phosphorus binders are given to patients with renal failure to increase gastrointestinal excretion of phosphorus. To determine the relative importance of the binding of dietary as compared with endogenous phosphorus and to determine the optimal dose schedule, we gave either 4.4 g of calcium acetate (25 mmol of calcium) or a placebo to six normal subjects on each of seven different schedules in a randomized sequence. The net gastrointestinal balance of phosphorus and calcium was determined by a one-day lavage technique. After a meal containing approximately 12 mmol of phosphorus, the mean phosphorus absorption (±SE) measured 9.17±0.36 mmol (78 percent) with placebo but decreased to 3.81±0.58 mmol (31 percent) when calcium acetate was given immediately before the meal (representing binding of 5.36±0.77 mmol of phosphorus). Similar binding was observed when calcium acetate was given immediately after the meal and when half the dose was given before and half after the meal. In contrast, when calcium acetate was given two hours after the meal or while the subject was fasting, phosphorus binding was reduced to 2.00±0.52 mmol and 1.81±0.84 mmol, respectively. Calcium absorption from calcium acetate averaged 21±1 percent when the binder was given with a meal; absorption from calcium acetate averaged 40±4 percent when the binder was given while the subject was fasting. We conclude that calcium acetate increases fecal excretion of phosphorus by binding both dietary and endogenous phosphorus, but the binding of dietary phosphorus is quantitatively much more important. For the most efficient phosphorus binding, calcium (and presumably other phosphorus-binding cations) should be given with meals. (N Engl J Med 1989; 320:1110–3.) PATIENTS with chronic renal insufficiency commonly use aluminum or calcium salts to bind phosphorus in the intestine and thereby reduce serum concentrations of phosphorus. 1 , 2 Potentially, such salts may bind either dietary or endogenous phosphorus. If their main effect is on dietary phosphorus, binders would presumably be more effective if ingested with meals. If, however, their main effect is to trap endogenous phosphorus, then the timing of ingestion may be less critical. The most effective schedule of administration is unknown. Experts vary in their recommendations: some advise patients to take phosphorus binders with meals, 1 some suggest that patients take them one . . .
doi_str_mv 10.1056/NEJM198904273201703
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_78951761</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>78951761</sourcerecordid><originalsourceid>FETCH-LOGICAL-c498t-7d3db1989756e0190c76b029ccab52ec626bd96dd7da6363d7cc03d281c1ea503</originalsourceid><addsrcrecordid>eNp9kE1r3DAQhkVISbab_IJQMCT0UtxoJFsfx-2y_WLzcUjORpbkrBZL3kr2If--NmtyKKFzmWHmmXeGF6ErwF8Bl-z2fvP7DqSQuCCcEgwc0xO0gJLSvCgwO0ULjInICy7pOfqY0h6PAYU8Q2eEw8jTBbrbNI3VfdY1Wb-z2ZPzdqpXxrvgUh9V77owddaq1W7w2UrbXvUjFLLHXZcOuy4OKfvmgnHh5QJ9aFSb7OWcl-j5--Zp_TPfPvz4tV5tc11I0efcUFNPn_OSWQwSa85qTKTWqi6J1Yyw2khmDDeKUUYN1xpTQwRosKrEdIk-H3UPsfsz2NRX3iVt21YF2w2p4kKWwBmM4PU_4L4bYhh_q0AIAoUoWTFS9Ejp2KUUbVMdovMqvlaAq8nq6h2rx61Ps_ZQe2vedmZvx_nNPFdJq7aJKmiX3jAmoRQwHf9yxLxPVbB7_9-jfwFXapBL</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1882148564</pqid></control><display><type>article</type><title>Effect of the Time of Administration of Calcium Acetate on Phosphorus Binding</title><source>MEDLINE</source><source>ProQuest Central</source><creator>Schiller, Lawrence R ; Ana, Carol A. Santa ; Sheikh, Mudassir S ; Emmett, Michael ; Fordtran, John S</creator><creatorcontrib>Schiller, Lawrence R ; Ana, Carol A. Santa ; Sheikh, Mudassir S ; Emmett, Michael ; Fordtran, John S</creatorcontrib><description>Phosphorus binders are given to patients with renal failure to increase gastrointestinal excretion of phosphorus. To determine the relative importance of the binding of dietary as compared with endogenous phosphorus and to determine the optimal dose schedule, we gave either 4.4 g of calcium acetate (25 mmol of calcium) or a placebo to six normal subjects on each of seven different schedules in a randomized sequence. The net gastrointestinal balance of phosphorus and calcium was determined by a one-day lavage technique. After a meal containing approximately 12 mmol of phosphorus, the mean phosphorus absorption (±SE) measured 9.17±0.36 mmol (78 percent) with placebo but decreased to 3.81±0.58 mmol (31 percent) when calcium acetate was given immediately before the meal (representing binding of 5.36±0.77 mmol of phosphorus). Similar binding was observed when calcium acetate was given immediately after the meal and when half the dose was given before and half after the meal. In contrast, when calcium acetate was given two hours after the meal or while the subject was fasting, phosphorus binding was reduced to 2.00±0.52 mmol and 1.81±0.84 mmol, respectively. Calcium absorption from calcium acetate averaged 21±1 percent when the binder was given with a meal; absorption from calcium acetate averaged 40±4 percent when the binder was given while the subject was fasting. We conclude that calcium acetate increases fecal excretion of phosphorus by binding both dietary and endogenous phosphorus, but the binding of dietary phosphorus is quantitatively much more important. For the most efficient phosphorus binding, calcium (and presumably other phosphorus-binding cations) should be given with meals. (N Engl J Med 1989; 320:1110–3.) PATIENTS with chronic renal insufficiency commonly use aluminum or calcium salts to bind phosphorus in the intestine and thereby reduce serum concentrations of phosphorus. 1 , 2 Potentially, such salts may bind either dietary or endogenous phosphorus. If their main effect is on dietary phosphorus, binders would presumably be more effective if ingested with meals. If, however, their main effect is to trap endogenous phosphorus, then the timing of ingestion may be less critical. The most effective schedule of administration is unknown. Experts vary in their recommendations: some advise patients to take phosphorus binders with meals, 1 some suggest that patients take them one . . .</description><identifier>ISSN: 0028-4793</identifier><identifier>EISSN: 1533-4406</identifier><identifier>DOI: 10.1056/NEJM198904273201703</identifier><identifier>PMID: 2710173</identifier><identifier>CODEN: NEJMAG</identifier><language>eng</language><publisher>Boston, MA: Massachusetts Medical Society</publisher><subject>Acetates - administration &amp; dosage ; Acetates - metabolism ; Acetic Acid ; Adult ; Biological and medical sciences ; Calcium - metabolism ; Drug Administration Schedule ; Eating ; Humans ; Intestinal Absorption ; Medical sciences ; Pharmacology. Drug treatments ; Phosphorus - metabolism ; Phosphorus - pharmacokinetics ; Time ; Urinary system</subject><ispartof>The New England journal of medicine, 1989-04, Vol.320 (17), p.1110-1113</ispartof><rights>1990 INIST-CNRS</rights><rights>Copyright Massachusetts Medical Society Apr 27, 1989</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c498t-7d3db1989756e0190c76b029ccab52ec626bd96dd7da6363d7cc03d281c1ea503</citedby><cites>FETCH-LOGICAL-c498t-7d3db1989756e0190c76b029ccab52ec626bd96dd7da6363d7cc03d281c1ea503</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/1882148564?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,64385,64387,64389,72469</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=6915814$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/2710173$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Schiller, Lawrence R</creatorcontrib><creatorcontrib>Ana, Carol A. Santa</creatorcontrib><creatorcontrib>Sheikh, Mudassir S</creatorcontrib><creatorcontrib>Emmett, Michael</creatorcontrib><creatorcontrib>Fordtran, John S</creatorcontrib><title>Effect of the Time of Administration of Calcium Acetate on Phosphorus Binding</title><title>The New England journal of medicine</title><addtitle>N Engl J Med</addtitle><description>Phosphorus binders are given to patients with renal failure to increase gastrointestinal excretion of phosphorus. To determine the relative importance of the binding of dietary as compared with endogenous phosphorus and to determine the optimal dose schedule, we gave either 4.4 g of calcium acetate (25 mmol of calcium) or a placebo to six normal subjects on each of seven different schedules in a randomized sequence. The net gastrointestinal balance of phosphorus and calcium was determined by a one-day lavage technique. After a meal containing approximately 12 mmol of phosphorus, the mean phosphorus absorption (±SE) measured 9.17±0.36 mmol (78 percent) with placebo but decreased to 3.81±0.58 mmol (31 percent) when calcium acetate was given immediately before the meal (representing binding of 5.36±0.77 mmol of phosphorus). Similar binding was observed when calcium acetate was given immediately after the meal and when half the dose was given before and half after the meal. In contrast, when calcium acetate was given two hours after the meal or while the subject was fasting, phosphorus binding was reduced to 2.00±0.52 mmol and 1.81±0.84 mmol, respectively. Calcium absorption from calcium acetate averaged 21±1 percent when the binder was given with a meal; absorption from calcium acetate averaged 40±4 percent when the binder was given while the subject was fasting. We conclude that calcium acetate increases fecal excretion of phosphorus by binding both dietary and endogenous phosphorus, but the binding of dietary phosphorus is quantitatively much more important. For the most efficient phosphorus binding, calcium (and presumably other phosphorus-binding cations) should be given with meals. (N Engl J Med 1989; 320:1110–3.) PATIENTS with chronic renal insufficiency commonly use aluminum or calcium salts to bind phosphorus in the intestine and thereby reduce serum concentrations of phosphorus. 1 , 2 Potentially, such salts may bind either dietary or endogenous phosphorus. If their main effect is on dietary phosphorus, binders would presumably be more effective if ingested with meals. If, however, their main effect is to trap endogenous phosphorus, then the timing of ingestion may be less critical. The most effective schedule of administration is unknown. Experts vary in their recommendations: some advise patients to take phosphorus binders with meals, 1 some suggest that patients take them one . . .</description><subject>Acetates - administration &amp; dosage</subject><subject>Acetates - metabolism</subject><subject>Acetic Acid</subject><subject>Adult</subject><subject>Biological and medical sciences</subject><subject>Calcium - metabolism</subject><subject>Drug Administration Schedule</subject><subject>Eating</subject><subject>Humans</subject><subject>Intestinal Absorption</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphorus - metabolism</subject><subject>Phosphorus - pharmacokinetics</subject><subject>Time</subject><subject>Urinary system</subject><issn>0028-4793</issn><issn>1533-4406</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1989</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9kE1r3DAQhkVISbab_IJQMCT0UtxoJFsfx-2y_WLzcUjORpbkrBZL3kr2If--NmtyKKFzmWHmmXeGF6ErwF8Bl-z2fvP7DqSQuCCcEgwc0xO0gJLSvCgwO0ULjInICy7pOfqY0h6PAYU8Q2eEw8jTBbrbNI3VfdY1Wb-z2ZPzdqpXxrvgUh9V77owddaq1W7w2UrbXvUjFLLHXZcOuy4OKfvmgnHh5QJ9aFSb7OWcl-j5--Zp_TPfPvz4tV5tc11I0efcUFNPn_OSWQwSa85qTKTWqi6J1Yyw2khmDDeKUUYN1xpTQwRosKrEdIk-H3UPsfsz2NRX3iVt21YF2w2p4kKWwBmM4PU_4L4bYhh_q0AIAoUoWTFS9Ejp2KUUbVMdovMqvlaAq8nq6h2rx61Ps_ZQe2vedmZvx_nNPFdJq7aJKmiX3jAmoRQwHf9yxLxPVbB7_9-jfwFXapBL</recordid><startdate>19890427</startdate><enddate>19890427</enddate><creator>Schiller, Lawrence R</creator><creator>Ana, Carol A. Santa</creator><creator>Sheikh, Mudassir S</creator><creator>Emmett, Michael</creator><creator>Fordtran, John S</creator><general>Massachusetts Medical Society</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>0TZ</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K0Y</scope><scope>LK8</scope><scope>M0R</scope><scope>M0T</scope><scope>M1P</scope><scope>M2M</scope><scope>M2O</scope><scope>M2P</scope><scope>M7P</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PSYQQ</scope><scope>Q9U</scope><scope>7X8</scope></search><sort><creationdate>19890427</creationdate><title>Effect of the Time of Administration of Calcium Acetate on Phosphorus Binding</title><author>Schiller, Lawrence R ; Ana, Carol A. Santa ; Sheikh, Mudassir S ; Emmett, Michael ; Fordtran, John S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c498t-7d3db1989756e0190c76b029ccab52ec626bd96dd7da6363d7cc03d281c1ea503</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1989</creationdate><topic>Acetates - administration &amp; dosage</topic><topic>Acetates - metabolism</topic><topic>Acetic Acid</topic><topic>Adult</topic><topic>Biological and medical sciences</topic><topic>Calcium - metabolism</topic><topic>Drug Administration Schedule</topic><topic>Eating</topic><topic>Humans</topic><topic>Intestinal Absorption</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Phosphorus - metabolism</topic><topic>Phosphorus - pharmacokinetics</topic><topic>Time</topic><topic>Urinary system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schiller, Lawrence R</creatorcontrib><creatorcontrib>Ana, Carol A. Santa</creatorcontrib><creatorcontrib>Sheikh, Mudassir S</creatorcontrib><creatorcontrib>Emmett, Michael</creatorcontrib><creatorcontrib>Fordtran, John S</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Pharma and Biotech Premium PRO</collection><collection>Nursing &amp; Allied Health Database</collection><collection>ProQuest Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>British Nursing Database</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>SciTech Premium Collection</collection><collection>New England Journal of Medicine</collection><collection>ProQuest Biological Science Collection</collection><collection>ProQuest Family Health</collection><collection>ProQuest Health Management</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest Psychology Journals</collection><collection>ProQuest research library</collection><collection>ProQuest Science Journals</collection><collection>ProQuest Biological Science Journals</collection><collection>Research Library (Corporate)</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest One Psychology</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><jtitle>The New England journal of medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schiller, Lawrence R</au><au>Ana, Carol A. Santa</au><au>Sheikh, Mudassir S</au><au>Emmett, Michael</au><au>Fordtran, John S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effect of the Time of Administration of Calcium Acetate on Phosphorus Binding</atitle><jtitle>The New England journal of medicine</jtitle><addtitle>N Engl J Med</addtitle><date>1989-04-27</date><risdate>1989</risdate><volume>320</volume><issue>17</issue><spage>1110</spage><epage>1113</epage><pages>1110-1113</pages><issn>0028-4793</issn><eissn>1533-4406</eissn><coden>NEJMAG</coden><abstract>Phosphorus binders are given to patients with renal failure to increase gastrointestinal excretion of phosphorus. To determine the relative importance of the binding of dietary as compared with endogenous phosphorus and to determine the optimal dose schedule, we gave either 4.4 g of calcium acetate (25 mmol of calcium) or a placebo to six normal subjects on each of seven different schedules in a randomized sequence. The net gastrointestinal balance of phosphorus and calcium was determined by a one-day lavage technique. After a meal containing approximately 12 mmol of phosphorus, the mean phosphorus absorption (±SE) measured 9.17±0.36 mmol (78 percent) with placebo but decreased to 3.81±0.58 mmol (31 percent) when calcium acetate was given immediately before the meal (representing binding of 5.36±0.77 mmol of phosphorus). Similar binding was observed when calcium acetate was given immediately after the meal and when half the dose was given before and half after the meal. In contrast, when calcium acetate was given two hours after the meal or while the subject was fasting, phosphorus binding was reduced to 2.00±0.52 mmol and 1.81±0.84 mmol, respectively. Calcium absorption from calcium acetate averaged 21±1 percent when the binder was given with a meal; absorption from calcium acetate averaged 40±4 percent when the binder was given while the subject was fasting. We conclude that calcium acetate increases fecal excretion of phosphorus by binding both dietary and endogenous phosphorus, but the binding of dietary phosphorus is quantitatively much more important. For the most efficient phosphorus binding, calcium (and presumably other phosphorus-binding cations) should be given with meals. (N Engl J Med 1989; 320:1110–3.) PATIENTS with chronic renal insufficiency commonly use aluminum or calcium salts to bind phosphorus in the intestine and thereby reduce serum concentrations of phosphorus. 1 , 2 Potentially, such salts may bind either dietary or endogenous phosphorus. If their main effect is on dietary phosphorus, binders would presumably be more effective if ingested with meals. If, however, their main effect is to trap endogenous phosphorus, then the timing of ingestion may be less critical. The most effective schedule of administration is unknown. Experts vary in their recommendations: some advise patients to take phosphorus binders with meals, 1 some suggest that patients take them one . . .</abstract><cop>Boston, MA</cop><pub>Massachusetts Medical Society</pub><pmid>2710173</pmid><doi>10.1056/NEJM198904273201703</doi><tpages>4</tpages></addata></record>
fulltext fulltext
identifier ISSN: 0028-4793
ispartof The New England journal of medicine, 1989-04, Vol.320 (17), p.1110-1113
issn 0028-4793
1533-4406
language eng
recordid cdi_proquest_miscellaneous_78951761
source MEDLINE; ProQuest Central
subjects Acetates - administration & dosage
Acetates - metabolism
Acetic Acid
Adult
Biological and medical sciences
Calcium - metabolism
Drug Administration Schedule
Eating
Humans
Intestinal Absorption
Medical sciences
Pharmacology. Drug treatments
Phosphorus - metabolism
Phosphorus - pharmacokinetics
Time
Urinary system
title Effect of the Time of Administration of Calcium Acetate on Phosphorus Binding
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-01T06%3A59%3A01IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Effect%20of%20the%20Time%20of%20Administration%20of%20Calcium%20Acetate%20on%20Phosphorus%20Binding&rft.jtitle=The%20New%20England%20journal%20of%20medicine&rft.au=Schiller,%20Lawrence%20R&rft.date=1989-04-27&rft.volume=320&rft.issue=17&rft.spage=1110&rft.epage=1113&rft.pages=1110-1113&rft.issn=0028-4793&rft.eissn=1533-4406&rft.coden=NEJMAG&rft_id=info:doi/10.1056/NEJM198904273201703&rft_dat=%3Cproquest_cross%3E78951761%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1882148564&rft_id=info:pmid/2710173&rfr_iscdi=true